tbuckley/cabot-search huggingface dataset:
Abstract 4409: Survival determinants of aggressive adult T-cell leukemia/lymphoma (ATLL): analysis of a pooled database
Authors: Supriya Gupta, Christopher Graham, Philip A. Haddad
Journal: Cancer Research (2023)

Abstract Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare Peripheral T-cell Lymphoma subtype caused by Human T-Lymphotropic Virus 1 (HTLV-1). The disease encompasses a vast phenotype ranging from the smoldering and chronic indolent subtypes to the lymphoma and acute aggressive subtypes. Aggressive ATLL which comprise acute/leukemic, lymphoma, and other indolent subtypes with aggressive transformation tend to have poor outcome with conventional chemotherapy rarely achieving durable lasting remission. We conducted this pooled database analysis to identify key factors that affect the clinical outcomes of aggressive ATLL subtypes. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 462 ATLL cases. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on the overall survival (OS). Results: Three hundred and forty-seven aggressive ATLL patients with survival data were included in this analysis. The median OS of the whole group was 14 months, with a median OS of 12.8, 16, and 12 months for acute, lymphoma, and transformed subtypes. The median age was 54 years, with a M:F ratio of 1.1. SCT demonstrated superior OS compared to chemotherapy (28 vs. 10 months, p&amp;lt;0.0001). Similarly, LSG15 regimens were superior to no chemotherapy and other combinations (29 vs. 1 vs. 15 months, p&amp;lt;0.0001). Asians and Afro-Caribbeans lived longer than Whites, Indians, and Hispanics (15.7, 15, 10, 3, 1 months, p&amp;lt;0.0001, respectively). The presence of hypercalcemia (Ca&amp;gt;11 mg/dl, Anemia (Hgb&amp;lt;12 g/dl), elevated LDH (&amp;gt;1000 U/L), and effusions adversely effected OS. Moreover, visceral involvement generally and specifically GI, kidney, lung, and heart were significantly detrimental to OS. However, age, sex and the presence of constitutional symptoms or HAM/TSP did not impact the OS. Conclusions: This study explored a wide array of clinical factors and their impact on the OS of aggressive ATLL. It identified race, types of treatment, the presence of hypercalcemia, anemia, elevated LDH, effusion and visceral metastases as significant determinants of OS in aggressive ATLL. Citation Format: Supriya Gupta, Christopher Graham, Philip A. Haddad. Survival determinants of aggressive adult T-cell leukemia/lymphoma (ATLL): analysis of a pooled database. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4409.
Abstract 5567: Circulating bacterial DNA is a non-invasive biomarker for early recurrence of NSCLC patients
Authors: Haiming Chen, Yiming Lu, Mantang Qiu
Journal: Cancer Research (2023)

Abstract Background: Alteration of human microbiota has been implicated in non-small cell lung cancer (NSCLC). However, most metagenomics studies utilized fecal samples, circulating bacteria DNA in patients with respectable NSCLC remain unexplored. This study aimed to characterize bacteria DNA in plasma of respectable NSCLC patients and build a machine-learning model to detect early recurrence of NSCLC. Methods: We performed whole genome sequencing of plasma from 101 NSCLC patients with (n = 36, R) or without (n = 65, NR) tumor recurrence within three years after surgery. Microbial DNA was obtained by removing the host genome and relative abundance was measured by mapping reads into microbial genomes. Significant microbial features were identified in the discovery set and built into a random forest model, which was tested in the validation set. Results: We enrolled 22 R and 39 NR patients with matching demographic features in the discovery set. The remaining 14 R and 26 NR patients were included in the validation set. PCoA analysis using Bray-Curtis distance showed significant differences between R and NR patients at genus level and species level in the discovery set. Notably, in the discovery set, 4 genera and 13 species showed significantly lower abundance in R patients, whereas 11 genera and 21 species were conversely enriched. Based on these significant microbial features, the random-forest model obtained the maximal AUC value of 0.9044 (95% CI, 0.8203-0.9886) when 11 features were selected. In the validation set, this model distinguished R from NR patients with an AUC of 0. 8434 (95% CI, 0.7189-0.9679). Conclusions: This pioneer study characterized alteration of circulating bacterial DNA in NSCLC patients with early recurrence, and illustrated significant difference in microbial composition between R and NR patients. The predictive model constructed with selected circulating microbial features was an accurate and non-invasive tool for prediction in early NSCLC recurrence. Citation Format: Haiming Chen, Yiming Lu, Mantang Qiu. Circulating bacterial DNA is a non-invasive biomarker for early recurrence of NSCLC patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5567.
Abstract 2361: Prevalence of mature tertiary lymphoid structures and association with tumor mutational burden in patients with solid tumors
Authors: Maxime Brunet, Lucile Vanhersecke, Francois Le Loarer, Isabelle Soubeyran, Antoine Italiano
Journal: Cancer Research (2023)

Abstract Background: Mature Tertiary Lymphoid Structures (mTLS) are organized lymphoid structures containing B-lymphocytes admixed to CD23+ follicular dendritic cells, which play a key role in antitumor immune response. We and others have demonstrated that presence of mature TLS is higly predictive of benefot of anti-PD1/PDL1 antibodies in patients with solid tumors (Vanhersecke et al Nature Cancer 2021, Italiano et al Nature Medicine 2022). However, the relative prevalence of mature TLS in the different tumor types has not been investigated with an uniform methodological approach. Methods: We screened the presence of mature TLS (mTLS) on tumor samples from patients included in an institutional molecular profiling program (BIP, NCT02534649). mTLS were screened using HES, CD20 (clone L26, Ventana) and CD23 (clone 1B12, Novocastra) stainings, performed on serial sections. TLS were defined as lymphoid aggregates of CD20+ B-lymphocytes of more than 50 immune cells within 1mm of the tumor front. mTLS were defined as TLS containing either a visible germinal center on HES or a meshwork of CD23+ follicular dendritic cells or isolated CD23+ dendritic cell if the cell harbored a morphology fitting with dendritic differentiation. If plasma sample of patient was available, bTMB was assessed by Foundation Medicine, with bTMB-high defined as at least 10 mutations/megabase (mut/Mb). Results: We characterized 1,393 samples. mTLS were present in 467 cases (33.5%) across all tumor histotypes: 36.2% of carcinoma (N = 392/1080 cases), 24.8% of sarcoma (N =69/209 cases) and 25% of neuroendocrine tumor (N= 4/12 cases). Among 569 cases with evaluable bTMB, the proportion of patients with bTMB-high was significantly higher in the mTLS group (16.7%, N=31/185) compared to absence of mTLS group (8.5%, N=30/353) (p=0.036). Conclusion: mTLS are present in variable proportions in almost all tumor types even in those considered as resistant to current immune checkpoint inhibitors. Prostate Bladder Kidney Head and neck Gynecologic (except ovary) Ovary mTLS+% of patients (N) 34% (28) 33% (19) 25% (6) 53% (17) 33% (19) 44% (26) mTLS-% of patients (N) 66% (55) 67% (38) 75% (18) 47% (15) 67% (39) 55% (32) Upper gastro intestinal tract Pancreatic Biliary tract Breast Thyroid Sarcoma mTLS+% of patients (N) 37% (19) 50% (13) 40% (21) 30% (38) 49% (24) 25% (69) mTLS-% of patients (N) 63% (33) 50% (13) 60% (32) 70% (90) 51% (25) 75% (209) Citation Format: Maxime Brunet, Lucile Vanhersecke, Francois Le Loarer, Isabelle Soubeyran, Antoine Italiano. Prevalence of mature tertiary lymphoid structures and association with tumor mutational burden in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2361.
Abstract 1048: Enabling higher sensitivity liquid biopsies with multiplex digital PCR NSCLC-relevant drug resistance panels
Authors: Michael Granitsiotis, Kimberly Gutierrez, Youxiang Wang, Jialuo Li, Zhijie Yang
Journal: Cancer Research (2023)

Abstract Cancers, for example, non-small cell lung cancer (NSCLC) and colorectal cancer, are frequently associated with specific genetic mutations that serving as biomarkers to guide more specific treatments (targeted therapy). The most frequently mutated genes include EGFR, KRAS, NRAS, BRAF, HER2, PIK3CA, MET, etc. Unfortunately, screening and monitoring the most common cancer related mutations and identifying the breadth of the most common drug-resistant mutations in MRD monitoring has previously required NGS - but cost, and time for execution, limits testing frequency. Furthermore, sensitivity is typically 1-5% VAF, thus limiting early detection. While digital PCR (dPCR) can be run at a fraction of the cost, and with higher sensitivity (VAFs of 0.1 to 0.01%), due to the lack of high level of multiplexing, it was historically impractical for routine screening. Here, we show that the use 6-color naica® system (Stilla Technologies), incorporating a series of high multiplex panels developed by Atila BioSystems, is able to group and efficiently detect the most frequently druggable mutations in a single reaction within three hours. Furthermore, we are demonstrating the coverage, precision, and sensitivity necessary to make high-plex digital PCR a viable option for future liquid biopsy testing. Citation Format: Michael Granitsiotis, Kimberly Gutierrez, Youxiang Wang, Jialuo Li, Zhijie Yang. Enabling higher sensitivity liquid biopsies with multiplex digital PCR NSCLC-relevant drug resistance panels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1048.
Abstract 5537: Prognostic impact of sarcopenia in patients with metastatic castration sensitive prostate cancer
Authors: Hiroaki Iwamoto, Kouji Izumi, Atsushi Mizokami
Journal: Cancer Research (2023)

Abstract Background/Aim: Recently, sarcopenia has been reported to be a useful prognostic factor in cancer patients, including prostate cancer patients. Gleason score, the presence or absence of visceral metastases, and the number of bone metastases, which were used in the LATITUDE and CHAARTED trials, are known prognostic factors for metastatic castration-sensitive prostate cancer (mCSPC). Although a large proportion of patients with mCSPC are elderly, the significance of sarcopenia in metastatic castration-sensitive prostate cancer is unknown. Patients and Methods: Of 193 patients with mCSPC treated at Kanazawa University Hospital between 2000 and 2019, 150 patients with confirmed CT at diagnosis were included. Sarcopenia was determined based on the definition of Martin et al. Overall survival and prognostic factors were retrospectively evaluated. Results: The median age was 72 years, median PSA 241 ng/mL, Gleason score (GS) ≥ 9 in 91 patients, visceral metastases in 23 patients, and sarcopenia in 106 patients. 109 patients (72.7%) were diagnosed as high risk by Latitude risk classification and 105 patients (70%) were diagnosed as high volume by Charted risk classification. All cause death was 64 patients, and the median follow-up period was 38.2 months. The median overall survival was 69.6 months. On multivariate analysis, GS ≥9 (P &amp;lt;0.0001, hazard risk =3.78), LDH ≥ 300 U/L (P &amp;lt;0.0001, hazard risk =2.88), and sarcopenia (P=0.04, hazard risk=2.07) were significant independent poor prognostic factors predicting shorter OS. The prognosis could be significantly stratified into a high risk group if two or more of these three factors were met and a low risk group if one or less was met (44 months vs. 106.4 months, P=0.0001, hazard risk=2.91). This classification more clearly stratified prognosis than the LATITUD classification (55.1 months vs. 135 months, P =0.027, hazard risk =1.8) or the CHAARTED trial classification (52.9 months vs. 135 months, P =0.009, hazard risk =1.98). Conclusion: Sarcopenia that can assess general status was considered useful in the prognostic evaluation of patients with mCSPC. Citation Format: Hiroaki Iwamoto, Kouji Izumi, Atsushi Mizokami. Prognostic impact of sarcopenia in patients with metastatic castration sensitive prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5537.
Efficacy of Tezepelumab in Severe, Uncontrolled Asthma: Pooled Analysis of the PATHWAY and NAVIGATOR Clinical Trials
Authors: Jonathan Corren, Andrew Menzies-Gow, Geoffrey Chupp, Elliot Israel, Stephanie Korn, Bill Cook, Christopher S. Ambrose, Åsa Hellqvist, Stephanie L. Roseti, Nestor A. Molfino, Jean-Pierre Llanos, Neil Martin, Karin Bowen, Janet M. Griffiths, Jane R. Parnes, Gene Colice
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Tezepelumab reduced exacerbations in patients with severe, uncontrolled asthma across a range of baseline blood eosinophil counts and fractional exhaled nitric oxide levels, and irrespective of allergy status, in the phase 2b PATHWAY (Study to Evaluate the Efficacy and Safety of MEDI9929 [AMG 157] in Adult Subjects With Inadequately Controlled, Severe Asthma; NCT 02054130) and phase 3 NAVIGATOR (Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; NCT 03347279) trials. Objectives: To examine the efficacy and safety of tezepelumab in additional clinically relevant subgroups using pooled data from PATHWAY and NAVIGATOR. Methods: PATHWAY and NAVIGATOR were randomized, double-blind, placebo-controlled trials with similar designs. This pooled analysis included patients with severe, uncontrolled asthma (PATHWAY, 18–75 years old; NAVIGATOR, 12–80 years old) who received tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. The annualized asthma exacerbation rate over 52 weeks and secondary outcomes were calculated in the overall population and in subgroups defined by inflammatory biomarker levels or clinical characteristics. Measurements and Main Results: Overall, 1,334 patients were included (tezepelumab, n = 665; placebo, n = 669). Tezepelumab reduced the annualized asthma exacerbation rate versus placebo by 60% (rate ratio, 0.40 [95% confidence interval, 0.34–0.48]) in the overall population, and clinically meaningful reductions in exacerbations were observed in tezepelumab-treated patients with type 2–high and type 2–low disease by multiple definitions. Tezepelumab reduced exacerbation-related hospitalization or emergency department visits and improved secondary outcomes compared with placebo overall and across subgroups. The incidence of adverse events was similar between treatment groups. Conclusions: Tezepelumab resulted in clinically meaningful reductions in exacerbations and improvements in other outcomes in patients with severe, uncontrolled asthma, across clinically relevant subgroups. Clinical trials registered with www.clinicaltrials.gov (NCT 02054130 [PATHWAY], NCT 03347279 [NAVIGATOR]).
Abstract 3909: THY1 regulates therapy resistance in glioblastoma recurrence
Authors: Sunita Shankar, Visweswaran Ravikumar, Hanxiao Wang, Sunjong Ji, Zainab Hasan, Ziad Fehmi, Yacoub Haydin, Daniel R. Wahl, Arvind Rao, Alnawaz Rehemtulla, Wajd Al-Holou
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM), is the most common primary brain tumor. It is a lethal disease with a median survival of 15 months characterized by treatment resistance, aggressive brain invasion, and inevitable recurrence. Less than 10 percent of patients survive beyond 5 years. Here, we developed an intracranial longitudinal in vivo recurrence model using HF2303, a patient derived explant, to produce paired specimens (pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR) treatment. Mouse brain tissues from the two groups were compared to identify genes and pathways driving treatment resistance. This analysis showed an elevated THY1 expression in recurrent HF2303 tumors compared to naïve tumors. Increased Thy1 expression was also associated with a more mesenchymal phenotype. THY1 expressing cells from naïve HF2303 were also resistant to TMZ/IR treatment in an intracranial model. In U87 neurospheres, overexpression of THY1 increased resistance to TMZ/IR. Interestingly, stable knockdown of Thy1 in GBM cells and human derived GBM organoids (GBOs) expressing high THY1 levels led to reduced cell proliferation. Yet, an inducible knockout of THY1 using CRISPR/Cas9 in human GBOs showed increased sensitivity to TMZ/IR. This suggests a clear link between THY1 expression and TMZ/IR resistance.Single cell RNA sequencing of over 25 primary GBM and 4 recurrent tumors (spanning over 120,000 cells) shows that cells expressing high levels of THY1 are associated with two distinct populations; neuronal precursor-like (NPC-like) and mesenchymal-like (MES-like). Furthermore spatial transcriptomics from 3 primary GBMs suggests that high THY1 expressing cells are colocalized with macrophages within the perivascular niche contributing to the mesenchymal phenotype. We will present these studies and our more recent work analyzing spatial recurrent GBM samples. Particularly, we will address how THY1 expression in these spatially distinct NPC-like and MES-like differ and how each of these states may contribute towards TMZ/IR resistance. Citation Format: Sunita Shankar, Visweswaran Ravikumar, Hanxiao Wang, Sunjong Ji, Zainab Hasan, Ziad Fehmi, Yacoub Haydin, Daniel R. Wahl, Arvind Rao, Alnawaz Rehemtulla, Wajd Al-Holou. THY1 regulates therapy resistance in glioblastoma recurrence. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3909.
Abstract 5144: Spatial T-cell atlas in more than 100 different tumor entities using BLEACH&amp;STAIN
Authors: Zhihao Huang, Elena Bady, Jan H. Müller, Tim Mandelkow, Magalie C. Lurati, Ronald Simon, Christian Bernreuther, Frank Jacobsen, Guido Sauter, Katharina Möller, Andreas Luebke, Andrea Hinsch, Till S. Clauditz, Eike Burandt, Niclas C. Blessin
Journal: Cancer Research (2023)

Abstract Background: The composition and functional state of T-cell subpopulations can highly impact patient’s outcome and response to immune checkpoint therapy. However, only little is known about the spatial interplay of most rare T-cell subpopulations. Design: To assess the density, composition, degree of immune checkpoint expression, and spatial interplay of T-cell subpopulations in 5989 tumor samples from more than 100 tumor entities, two different types of tissue microarrays (0.6 mm and 4 mm in diameter) were stained with antibodies directed against CD3, CD4, CD8, FOXP3, T-bet, GATA3, RORyT, BCL6, FOXP3, CD56, CD45RA, CD45RO, TIM3, PD-1, CTLA-4 Granzym B, and Ki67 using our BLEACH&amp;STAIN multiplex fluorescence immunohistochemistry approach. A deep learning-based framework comprising two different convolutional neuronal networks (U-Net and DeepLabv3+) was used for image analysis. Results: For identification and definition of immune cell subpopulations unsupervised X-shift clustering and 2D/3D t-distributed stochastic neighbor embedding (t-SNE) using the “Rtsne” package (Rtsne (RRID:SCR_016342)) were applied and revealed 102 T-cell subpopulations at certain functional state. Within these subpopulations, the well-characterized expression profiles were visually matched with single T-cell expression profiles and documented as digital images. This process resulted in 12 main T-cell subsets that were further subclassified according to their functional state (proliferation, immune checkpoint expression) and studied according to their spatial orchestration. Interestingly, the vast majority of T-cell subsets were found in all analyzed tumor entities. However, their spatial orchestration, immune checkpoint expression profile was highly variable between different tumor entities. Conclusion: This study provides a comprehensive overview of rare T-cells subpopulations and its spatial orchestration in more than 100 different tumor entities. Citation Format: Zhihao Huang, Elena Bady, Jan H. Müller, Tim Mandelkow, Magalie C. Lurati, Ronald Simon, Christian Bernreuther, Frank Jacobsen, Guido Sauter, Katharina Möller, Andreas Luebke, Andrea Hinsch, Till S. Clauditz, Eike Burandt, Niclas C. Blessin. Spatial T-cell atlas in more than 100 different tumor entities using BLEACH&amp;STAIN. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5144.